This R03 (ECHEM) proposal plans to explore novel strategies to accelerate the progress of searching for novel analgesic and anti-inflammatory agents. It is known that research on analgesic and anti-inflammatory agent has been among the most active topics in medicinal and pharmaceutical sciences in the past several decades. So far, nearly all of known analgesic and anti-inflammatory agents on the market have been proven to show physiological effects, such as supraspinal analgesia, respiratory depression, miosis, euphoria, nausea, and reduced gastrointestinal motility. These undesirable effects have resulted in serious medical problems for numerous patients and their families worldwide. The search for new agents, particularly, for those of concise and small molecules still remains important and challenging. In this proposal libraries consisting a series of novel N-a,a-cyclic acyl glycines and ethanolamides, N-acyl a,a-cyclic glycines and cyclic ethanolamides have been designed and will be synthesized so as to control their structural flexibility and to maximize their binding affinities and biological activities. Meanwhile, new chiral amino alcohols and diamines for N-acyl glycine and ethanolamide mimetics as well as their libraries will be synthesized. The novel chiral N-phosphonimine chemistry invented by the PI's group will be employed for the synthesis of b-hydroxy a-amino acids and 1-hydroxy vicinal amino alcohols that are precursors of N-arachiodonoyl ethanoamides. In addition, the asymmetric diamination reaction will be studied for asymmetric synthesis of a,a-diamino acids and corresponding 1-hydroxy vicinal diamines. The pharmacological profiles of resulting novel analgesic and anti-inflammatory agents will be evaluated. The PI's group has trained nearly 50 undergraduate students and 14 graduates for conducting organic and bioorganic research. All graduates and 25 of undergraduates achieved research publications with the PI. Most of these students successfully entered medical schools. The present NIH-R03 project will greatly benefit the PI's undergraduates and graduate education at Texas Tech University. The co-PI, Professor Sumner Burstein at University of Massachusetts Medical School has been working in the area of cannabinoids since 1968. His efforts were originally focused on the metabolism of cannabinoids and resulted in the discovery of the oxidative metabolic pathway of tetrahydrocannabinol (THC). The terminal product of this pathway is THC-11-oic acid, which has served as a template for the discovery of a synthetic analog, ajulemic acid, a potent analgesic and anti-inflammatory agent with greatly reduced psychotropic activity. Ajulemic acid is currently undergoing commercial development for the treatment of chronic pain. Most recently, the co-PI has been working in the area of the endogenous cannabinoids exemplified by the eicosanoid arachidonoyl ethanolamide. An analog, or possible metabolite of anandamide, N-arachidonoyl glycine (NAGly), was discovered which led to the further discovery of a family of acyl amino acid analogs. These molecules, called elmiric acids, have been shown to have potential as novel anti-inflammatory agents. The experience of the PI and co-PI on this topic makes this grant proposal feasible. PUBLIC HEALTH RELEVANCE: This proposal plans to find new analgesic and anti-inflammatory agents to potentially replace the traditional drugs that have been used for a long time. Innovative strategies including the use of N- a,a-cyclic acyl glycines and ethanolamides, N-acyl a,a-cyclic glycines and cyclic ethanolamides will be explored. The new candidates can avoid, or at least minimize undesirable effects such as addiction,respiratory depression, drug dependence and many other related side effects that exist in all known drug. Thus far, the PI's group has trained more than 50 undergraduate students and 16 graduates in conducting research in organic/medicinal research. All graduates and more than 20 of undergraduates achieved research publications with the PI. All of these students either successfully entered medical schools or found jobs in pharmaceutical companies. The present NIH-R15 grant will greatly benefit PI's undergraduate and graduate education and help the PI to attract more students into sciences.